Despite impressive advances in the treatment of atherosclerosis, the residual burden of disease remains huge and many aspects of atherogenesis and its complications are poorly understood. These include genetic factors influencing atherosclerosis independent of traditional risk factors, molecular and cellular determinants of atherosclerotic plaque progression, and mechanisms responsible for accelerated atherosclerosis in diabetes or low HDL states. The major goal of the PPG is to elucidate new genes and pathways involved in atherosclerosis, especially as they relate to these unsolved problems. The approach will be to use transgenic mice, mouse genomic information and innovative cellular models. Major themes include the role of cellular apoptosis in atherosclerosis and plaque progression, the role of defects in cellular cholesterol uptake, efflux or trafficking in atherogenesis and the use of mouse genetics and induced mutant mouse models to identify novel genes involved in atherosclerosis and plaque progression. In Project 1: Dr. Breslow will explore the hypothesis that the modulation of TNF signaling by different genetic variants of the A20 gene results in altered vascular cell apoptosis and atherosclerosis, and will seek to identify additional atherosclerosis modifier genes on mouse chromosome 10. In Project 2: Dr. Tabas will define new signaling pathways mediating free cholesterol-induced macrophage apoptosis and explore their in vivo significance in mouse models of atherosclerosis and plaque progression. In Project 3: Dr. Tall will evaluate the cellular mechanisms and in vivo role in atherogenesis of the recently identified transporter, ABCG1, that mediates the efflux of cholesterol from macrophage foam cells to HDL. In Project 4: Dr. Goldberg will evaluate a recently developed model of accelerated diabetic atherosclerosis, the aldose reductase transgenic mouse, and will explore underlying mechanisms. Overall, this is a well integrated, highly collaborative program that will use innovative genetic and cell biological approaches to provide new insights into major unsolved problems in atherogenesis.